Cocaine addiction is a serious public health problem. There are no FDA approved medications for the treatment of cocaine addiction. Previous studies have shown that phosphodiesterase-4 (PDE-4) inhibitor rolipram reduces addictive behavior by multiple drugs of abuse in multiple behavior assays and the ventral tegmental area (VTA) is a primary site that mediates its action. Considering that PDE4 and non-selective PDE inhibitors ameliorate aging-related metabolic phenotypes in animal studies and show effectiveness in treating respiratory diseases and depression in clinical trials, these inhibitors are a promising candidate for developing anti-addiction medications with potential health benefits. The goal of this project is to investigate neural circuits and downstream signaling mechanisms that mediate PDE inhibitor-induced attenuation of cocaine conditioned place preference (CPP) and locomotor sensitization. The central hypothesis is that the PDE inhibitors reduce the behavioral effects of cocaine through activation of exchange proteins activated by cAMP (Epac) and inhibition of the mammalian target of rapamycin (mTOR) signaling in the VTA. The hypothesis will be tested through three Specific Aims: 1) Test if the PDE inhibitors activate Epac signaling in VTA dopamine neurons to attenuate cocaine-induced CPP and locomotor sensitization. Under this Aim, we will use the designer receptors exclusively activated by designer drugs (DREADD) technology to interrogate the neuronal cell-type that mediates the action of PDE inhibitors. We will examine whether disruption of Epac signaling in the VTA abrogates the behavioral effects of the PDE inhibitors. 2) Investigate synaptic mechanisms by which the PDE inhibitors attenuate cocaine CPP. Under this Aim, we will test the hypothesis that the PDE inhibitors induce long-term depression-like synaptic modification, which neutralizes cocaine-evoked synaptic potentiation and provides a potential mechanism for the reduction in cocaine CPP induced by PDE inhibitors. 3) Test whether PDE inhibitors reduce cocaine CPP and locomotor sensitization through inhibition of mTOR signaling. Under this Aim, we will use a cre-loxP system to produce conditional knockout of mTOR in the VTA and examine its impact on cocaine-induced CPP and behavioral sensitization and behavioral changes induced by the PDE inhibitors. The identification of downstream targets and molecular mechanisms that mediate the action of the PDE inhibitors is a critical first step toward repurposing PDE inhibitors for anti-addiction medications.